Mechanisms that link innate and adaptive immunity play a central role in immune responsiveness and are a promising area of investigation for the discovery of novel immune adjuvants. In the oral cavity, human beta defensins that are produced by epithelial cells may mediate crosstalk between innate and adaptive defenses. These molecules have anti-microbial properties but also mediate chemotaxis of antigen-presenting cells. Our work has characterized for the first time, the ability of human beta defensin-3 to activate antigenpresenting cells in a toll-like receptor-dependent manner. The proposed studies will explore the effects of this interaction in the maturation of human antigen-presenting cells and in the development of T cell immunity. Cell signaling assays and proteomics analyses will be utilized to ascertain the effects of beta defensin-3 in human antigen-presenting cells and to compare these responses with those induced by other toll-like receptor agonists. The function and phenotype of naTve T cells will also be assessed after activation of these cells with beta defensin-primed antigen-presenting cells. The proposed studies include a determination of the structural properties of human beta defensin-3 that account for its toll-like receptor agonist activity. These studies involve utilization of chimeric and mutated defensin molecules to examine their toll-like receptor agonist activity. Finally, the proposed studies examine the responsiveness of antigenpresenting cells from HIV-infected persons to the activating signals provided by beta defensin-3 and other toll-like receptor agonists to explore the hypothesis that reduced responsiveness to beta defensins in HIV disease may predispose these persons to oral complications. These studies have important implications for developing defensin molecules as oral vaccine adjuvants and for understanding defensin biology in the context of chronic HIV infection.